Cleaning Validation, Purpose:
Cleaning Validation, To lay down a procedure for carrying out cleaning validation to establish validated cleaning procedure for manufacturing and primary packaging equipment and effectively maintain cleaning process in validated state. Cleaning must be demonstrated to be effective in order to provide assurance that unacceptable levels of contamination are not carried over into subsequent products. It defines the cleaning validation and verification requirements to ensure that all cleaning procedures which may impact product quality are formally validated or verified. Cleaning must be demonstrated to be effective in order to provide assurance that unacceptable levels of contamination are not carried over into subsequent products. It defines the cleaning validation and verification requirements to ensure that all cleaning procedures which may impact product quality are formally validated or verified.
Cleaning Validation, Scope:
This procedure is applicable for equipment’s used in product manufacturing and primary packaging of XX Pharmaceuticals Limited (Both General & Cephalosporin Block).
Definitions / Abbreviation:
[][]QA : Quality Assurance
[][]QC : Quality Control
[][]CIP : Clean-in-place
[][]OOS : Out of Specification
[][]MACO : Maximum Allowable Carryover
Responsibilities:
[][]The roles and responsibility is as follows:
Concerned Department
[][]To cooperate the validation team to make the cleaning validation job successful.
Quality Assurance
[][]Responsible for the developing and co-ordinate the entire cleaning validation activities as a team leader.
Quality Control
[][]Ensure that analytical method has been prepared and validated before conducting cleaning validation and coordinate all analytical & Microbiological test.
To coordinate all the sampling activities.
Head of Plant Operation
[][]Proper follow-up of overall activities.
Head of Quality Assurance
[][]Approval of all the validation activities.
Procedure:
[][]Prior to conducting a cleaning validation study on an Active Ingredient (of previous product) following activities need to be summarized. A Validation team shall be formed comprising of members from Production, Engineering, Quality Control, Validation / Quality Assurance.
Defining the key elements
[][]Define solubility, toxicity of active ingredient in cleaning validation protocol. If any of the active ingredients are deemed to be more potent or less soluble in water than the ingredients for which cleaning validation has already been completed, or deemed to be particularly difficult to clean from equipment, a new validation study will be carried out.
[][]Define the product-equipment matrix.
[][]Prepare the equipment matrix. Determine the total contact surface area of the equipment/ instruments which are to be used in the manufacturing of that product with the help of Engineering and Production Department.
[][]Determine the scope and establish acceptance criteria.
[][]Develop and validate sampling procedure and analytical method.
[][]Designing the cleaning validation protocol. All protocols shall be as per the Format given I Annexure- I.
[][]Execute the cleaning validation study and protocol.
[][]Summarize the data and compilation of the final report.
[][]Devising and monitoring program to establish that the cleaning process is continued to be in validated state.
[][]Establishing conditions for which re-validation would be required.
Describing the key elements
[][]The product – equipment matrix
[][]Prepare a Product–equipment matrix (Annexure-II) & Equipment matrix (Annexure-III) for the products, equipments used in the cleaning validation study.
[][]The matrixes will provide information about the manufacturing and packing line used for multiple products and possible product contact surface area.
[][]The matrix will indicate the worst case at a glance and justify the acceptance criteria for a cleaning validation.
Determining the scope
[][]The scope includes evaluation of residual contamination of active ingredient.
[][]Cleaning validation to be done based on matrix for including any new product in to the matrix for supplying product to local market. However, all products deemed to be supplied to highly regulated markets, the cleaning validation to be done for every product.
[][]Acceptance criteria for Residual active ingredients: The approach for setting limits can be (1) product specific cleaning validation for all products; (2) grouping into product families and choosing a worst case product; (3) grouping into groups of risk (e.g. cleaning difficulty, solubility, toxicity potency of API, facility volume of product); (4) setting limits on not allowing more than a certain fraction of carryover; (5) different safety factors for different dosage forms.
[][]For determining cleaning validation process, widely used criteria, i.e. 1/1000, will be consider for MACO calculation and to evaluate the cleaning effectiveness.
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.
MACO = TDD Previous X MBS/ SF X TDD Next
Where,
=>MACO = Maximum Allowable Carryover: acceptable transferred amount from the investigated product ( “previous” )
=>TDD Previous = Standard therapeutic dose of the investigated product ( in the same dosage form as TDD next)
=>TDD Next = Standard therapeutic dose of the daily dose for the next product.
=>MBS = Minimum Batch Size for the next product(s) (where MACO can end up)
=>SF = Safety Factor ( normally 1000 is used in calculation based on TDD )
#(Ref. APIC : Active Pharmaceutical Ingredients Committee)
[][]However, the other criteria i.e. 10 ppm Criteria, API toxicity data will also be taken into consideration for evaluation of cleaning effectiveness. The cleaned equipment’s will also be checked visually to ensure the cleaning effectiveness.
[][]1/1000 Criteria: NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product.
[][]10 ppm Criteria : NMT 10 ppm of any product to appear in another product;
[][]Based on toxicity : LD50 Value of API will be considered;
[][]Visual Inspection: No quantity of residue to be visible on the equipment after cleaning procedures is performed.
[][]API Solubility: The solubility of drug in washing solvent plays a great role in cleaning. The lesser the solubility greater will be the difficulty to remove the residue from surface.
[][]Thus least soluble molecule (based on the pharmacopoeia or other reliable reference) will be taken for the analysis since if least soluble molecule gives satisfactory result in cleaning validation and routine monitoring then we can rest assure for the other higher soluble drug.
[][]API Toxicity: An evaluation according to the toxicities should be carried out based on the material safety data sheet (MSDS).
[][]Other risk factors such as potency and facility volume of a particular product should also be taken into consideration during designing cleaning validation program.
[][]Develop and validate analytical method for cleaning validation sample analysis.
Swab sampling
[][]Generally method involves swabbing of 5 cm2 but larger area could be considered as per regulatory dossier or with proper justification and difficult to clean areas will be considered as per below Diagrammatic representation.
[][]Define the most difficult to clean areas in the piece of equipment (show delineate pictorially as far as possible).
[][]A polyester tipped swab (Texwipe, Alpha swab with long handle) shall be used. One side of swab shall be given horizontal 10 strokes and then reverse side of the swab shall be given vertical 10 strokes.
[][]The swab stick shall be dipped into the screw cap test tubes/ vials containing solvent (Approximately 10 ml). One test tube / vial will be taken for each swab sample.
[][]The test tube / vial will be labeled specifying the particular piece of equipment swabbed & the location (where appropriate).
[][]The soaked swab (in solvent) to be firmly squeezed along the side of the test tubes / vials and then sampling side to be swabbed. After taking samples from the equipment/utensils the swab to be returned to the respective screw cap test tube/vial.
[][]Each vial will be closed with swab inside & sent to QC for analysis of the swab sample.
[][]Study and establish the stability of sample solution storage condition & storage time, based on a protocol.
[][]Perform the recovery analysis on the swab with spiked SS surface/ similar to the equipment material of construction. Recovery of drug shall be not less than 85% after taking into account interference of swabbing material.
[][]Perform the recovery study of the API from the swab stick for record only.
[][]Mention the swab sampling point details in the cleaning validation protocol.
Rinse sampling
[][]For rinse sample collection graduated plastic mug/container, plastic squeezer, stainless steel container to be used, will be cleaned first with 70% IPA followed by sufficient purified water (Wipe with lint free cloth soaked in 70% IPA if required after visual inspection).
[][] After collection of each rinse the required quantity will be transferred to the conical flask for QC submission. To discard the leftover residue in the SS container/ plastic mug these utensils will be cleaned with sufficient purified water before next use.
[][]Same procedure will be followed for MDI unit except for cleaning purpose only absolute ethanol will be used instead of 70% IPA and purified water.
[][]Rinse sample can be evaluated at intervals during the cleaning and at the completion of the cleaning process. Collection of rinse samples should consider location, timing and volume.
[][]Rinse sample allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment.
[][]Study and establish the stability of sample storage conditions and storage time, based on a protocol.
[][]For those equipment or parts (e.g. turret, die and punch of compression machine, hopper) rinse sampling method is not feasible, only swab sampling method will be applied.
[][]At first swab sample will be collected as per plan and will be sent to QC. Then the swab taken area will be cleaned with purified water and finally with lint free cloth.
[][]At first the equipment will be cleaned as per the equipment cleaning SOP and the dismantled parts will be stored in the clean equipment store room after drying.
[][]After collecting rinse samples the cleaned equipment’s will be allowed for self drying before next use. Finally the rinse sample in a closed conical flask with proper labeling will be sent to QC for analysis.
[][]Perform the recovery analysis on the rinse with spiked SS surface/ similar to the equipment material of construction. Recovery of drug shall be not less than 85%.
[][]Microbiological considerations: weather or not CIP systems are used for cleaning of processing equipment, consider the microbiological aspects of equipment cleaning.
[][]The equipment/utensils are considered clean if the total microbial count is less then 25 CFU per 25 cm2/ per swab or 100 cfu/ml taken from equipment/utensils surface and there are no objectionable organisms present ( e.g. E.coli, Salmonella, Pseudomonas aeruginosa, Staphylococcus aureus).
[][]If any growth is observed, appropriate tests to identify the organisms are to be conducted. If the acceptance limit is exceeded, or an objectionable microorganism is identified, then then an OOS investigation must be initiated by the Microbiological Laboratory to identify the source of microbial contamination. Investigation should be done by the manufacturing department.
[][]Contaminated equipment must be re-cleaned and re-swabbed/re-rinsed and it be must meet acceptance limits prior to release for further manufacturing.
For all the types of equipment initial cleaning validation shall be performed on at least three consecutive batches or three runs.
Bracket Approach
[][]The design uses the extremes to cover in between range. That is the largest pieces of identical equipment could cover all of the in between sizes.
[][]The lowest and highest strength of the products.
Worst Case Approach
[][]The most difficult to clean equipment could cover all the easier to clean equipment also.
[][]Initially cover all the types of equipment for three runs.
[][]Type A cleaning done after 6 days (144 hours) from the first day of use of the equipment or area of solid dosage forms.
[][]The dirty holding period of manufacturing equipment should not be more than 5 days.
[][]In case of batch size change, either increase or reduction in the batch size, the matrix shall be re-evaluated.
[][]If a drug product is manufactured in different strengths, cleaning procedures shall be validated for the highest strength of that particular drug product. If the manufacturing line contains multiple products or a single product contains multiple active ingredients, the active ingredient which is least soluble/more in concentration and/or more toxic, hard to clean shall be taken into consideration for cleaning validation/verification.
[][]If there are multiples of particular equipment with same configuration, material of construction and cleaning procedure then cleaning validation of one piece of that particular equipment will be adequate.
[][]If there are different sizes of the same equipment with same cleaning procedure, cleaning validation for the largest size of that particular equipment is adequate.
[][]The worst case selection criteria will be a) Hard to clean product (Color and Flavor) b) Least soluble API c) Maximum toxicity of API d) Minimum therapeutic daily dose e) Facility volume of a particular product.
Execution of cleaning validation protocol/study
[][]Adequate training to the operators (Production, QC and Engineering) shall be given and documented to execute the protocol efficiency.
[][]Ensure that during validation study the results and activities represent regular daily operations.
[][]Ensure that the same piece of equipment is available for the execution of the cleaning by the operators.
[][]Ensure that operator’s variability is addressed during the process design to maximize the representation of results.
=>Cleaning Validation Protocol number shall be given as follow;
CVR/XXX/YY
Where
=>CVP stands for Cleaning Validation Protocol/stands for separator
=>XXX stands for the sequential number which starts from 001 for calendar year.
=>YY stands for the last two digit of the year.
Summarize the data and generate the report
[][]The final result of particular sampling site shall be ‘difficult to clean’ reported and incorporated in the calculations.
[][]Test results shall be complied by Validation/QA.
[][]Any change in procedure shall be approved by QA.
[][]Evaluation of product matrix shall be done periodically or during introduction of any new product into the existing facility.
[][]Objective & Scope: Describe the objective and scope of the cleaning validation / verification in cleaning validation /verification protocol.
[][]Cleaning Validation/Verification Protocol: provides the tabulated test results and the acceptance criteria for each piece of equipment and equipment train.
[][]Cleaning Validation/Verification process shall be concluded with a summarized report incorporated as a final report, which is written and approved.
[][]Tabulation of test results: provides the tabulated test results and mention the acceptance criteria for each piece of equipment and equipment train.
[][]Discussion and Conclusion: discuss the cleaning validation program under study and summarize the outcome of the cleaning validation program.
[][]Cleaning Validation Report number will be same as protocol no. given as follows.
=>CVR/XXX/YY
=>Where, CVR stands for Cleaning Validation Report.
=>Revalidation of cleaning procedure is required in case of following change
=>Equipment or equipment configuration changes.
=>Changes in cleaning procedure and change of formulation where active quality is increased (e.g. overage).
=>Change in acceptance criteria due to change in batch size or introduction of new product (the matrix shall be Re-evaluated by preparing a separate cleaning validation protocol).
=>Process change in manufacturing process (e.g. wet granulation to direct compression and vice versa).
=>The significance of change shall be evaluated collectively by Production, Engineering and QA.
=>Whenever any change control is made to a validated cleaning procedure, due to change in equipment, process, repair or any other valid reason, then the need evaluation shall be done jointly by the Head of Production, Head of Engineering and finally approved by Manager QA.
=> If the decision is made to revalidate, the same be implemented.
Annexure:
Annexure I-Cleaning Validation Protocol
Annexure II-Product Equipment Matrix
Annexure III-Equipment Matrix